7-fluoro-dihydro PGI compounds

ABSTRACT

7-fluoro-16-substituted 15-hydroxy PGI 2  compounds which have saturated bond of the 13 position and which are useful as blood platelet anti-aggregating agents.

BACKGROUND AND STATEMENT OF PRIOR ART

Prostacyclin (PGI₂) is a potent vasodilator and a potent inhibitor ofplatelet aggregation. These properties are opposite to those produced bythromboxane A₂ (TXA₂) which like PGI₂ is a major metabolite of theprostaglandin endoperoxides PGH₂ and PGG₂. Generally, prostacyclins invivo prevent the attachment of platelet aggregates to blood vessel wallsthereby inhibiting blood platelet aggregation while also lowering bloodpressure.

7-halo PGI₂ derivatives have been described and found useful forinhibiting blood platelet aggregation while lowering blood pressure. Seefor example British patent application No. 2,094,310--Holland, Maag andRosen published Sept. 15, 1982; British patent application2,088,856--Szekely et al. published June 19, 1982 and U.S. Pat. No.4,472,428--Toru et al. issued Sept. 18, 1984.

Prostacyclins as therapeutic agents suffer from the inherentdisadvantage that they contain a labile enol ether moiety which causesinstability. In addition prostacyclins can be used both for their bloodpressure lowering and platelet anti-aggregation effect. Therefore, aprostacyclin which is stable and which provides a separation between theanti-aggregation property and the blood pressure lowering effect isideally suited for use as a therapeutic agent.

SUMMARY OF INVENTION

In accordance with this invention, compounds of the formula ##STR1##wherein R is hydrogen or lower alkyl; R₂ is hydrogen, methyl or fluoro;and R₂ ' is fluoro, hydrogen, trifluoromethyl or methyl; and with theproviso that when R₂ ' is trifluoromethyl, R₂ is hydrogen or methyl andsalts thereof as well as optical antipodes and racemates thereof areuseful as a blood platelet anti-aggregating agents. In particular, thecompounds of formulae I-A provide a separation of properties since theyexhibit strong a blood platelet anti-aggregating affects withoutsubstantially reducing blood pressure. In addition, these compounds showa high degree of stability.

The compounds of formulae I-A and I-B are prepared from compounds of theformula: ##STR2## wherein R₂ and R₂ ^(') are as above; R₃ and R₄individually are hydrogen or when taken together with their attachedoxygen atom form an ether or ester protecting group;

or optical antipodes or racemates thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this application, the term "lower alkyl" includesboth straight chain and branched chain alkyl groups having from 1 to 7carbon atoms such as methyl and ethyl. As also used herein, the term"lower alkanoic acids" comprehends an alkanoic acid of 1 to 7 carbonatoms such as formic acid and acetic acid. As further used herein, thethe term "halogen" or "halo", unless otherwise stated, comprehendsfluorine, chlorine, bromine and iodine. Alkali metal includes all alkalimetals such as lithium, sodium and potassium.

In the process of this invention, all compounds having one or moreasymmetric carbon atoms can be produced as racemic mixtures. Theseracemic mixtures which are obtained can be resolved at the appropriatesteps in the process of this invention by methods well known in the artwhereupon subsequent products may be obtained as the correspondingoptically pure enantiomers. On the other hand, the claimed opticallyactive enantiomer or racemates of formula I can be produced dependingupon the optical form of the compound of formula II utilized as astarting material.

In the pictorial representation of the compounds given throughout thisapplication, a thickened taper line indicates a substituent which is inthe beta-orientation (above the plane of the molecule), a dotted line () indicates a substituent which is in the alpha-orientation (below theplane of the molecule) and a wavy line indicates a substituent which isin either the alpha- or beta-orientation or mixtures of these isomers.It is to be understood that the pictorial representations of thecompounds given throughout the specification are set forth forconvenience and are to be construed as inclusive of other formsincluding enantiomers and racemates and are not to be construed aslimited to the particular form shown.

As also used herein, the term "aryl" signifies mononuclear aromatichydrocarbon groups such as phenyl, which can be unsubstituted orsubstituted in one or more positions with a lower alkylenedioxy, nitro,halo, a lower alkyl or a lower alkoxy substituent, and polynuclear arylgroups such as naphthyl, anthryl, phenanthryl, azulyl, etc., which canbe unsubstituted or substituted with one or more of the aforementionedgroups. The preferred aryl groups are the substituted and unsubstitutedmononuclear aryl groups, particularly phenyl.

The term "ether protecting group removable by acid catalyzed cleavage"designates any ether which, upon acid catalyzed cleavage yields thehydroxy group. A suitable ether protecting group is, for example, thetetrahydropyranyl ether, or 4-methoxy-tetrahydropyranyl ether. Othersare arylmethyl ethers such as benzyl, benzylhydryl, or trityl ethers oralpha-lower alkoxy lower alkyl ether, for example, methoxymethyl ortri(lower alkyl)silyl ethers such as trimethyl silyl ether;diphenyl-t-butyl silyl ether or dimethyl-tert-butyl silyl ethers. Thepreferred ether protecting groups which are removed by acid catalyzedcleavage are t-butyl and tetrahydropyranyl and the tri(lower alkyland/or aryl)silyl ethers, particularly dimethyl-tert-butyl silyl etherand diphenyl-t-butyl silyl ether. Acid catalyzed cleavage is carried outby treatment with an organic or inorganic acid. Among the preferredinorganic acids are the mineral acids such as sulfuric acid, hydrohalicacid, etc. Among the preferred organic acids are lower alkanoic acidssuch as acetic acid, para-toluene sulfonic acid, etc. The acid catalyzedcleavage can be carried out in an aqueous medium or in an organicsolvent medium. Where an organic acid or alcohol is utilized, theorganic acid or alcohol can be the solvent medium. In the case oftetrahydropyranyl ethers, the cleavage is generally carried out in anaqueous medium. In carrying out this reaction, temperature and pressureare not critical and this reaction can be carried out at roomtemperature and atmosphere pressure.

The term "ester protecting group" describes ester protecting groupswhere the hydroxy substituent is protected by esterification with anorganic acid to form a hydrolizable ester. Among the preferred esterswhich can be utilized to protect the hydroxy group are those estersformed by reacting the hydroxy group with a lower alkanoic acidcontaining from 1 to 7 carbon atoms present as acetic acid, propionicacid, butyric acid, as well as aroic acids such as benzoic acid and aryllower alkanoic acids where aryl is defined as above and the loweralkanoic acid contains from 2 to 7 carbon atoms.

That the 7-fluoro prostacyclins are potent blood plateletanti-aggregating agents can be seen when the following compounds:

CompoundA=(5Z,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-dihydroxy-prost-5-en-1-oicacid monosodium salt; and

CompoundB=(5Z,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-prost-5-en-1-oicacid monosodium salt;

were tested against PGI₂ for their blood platelet anti-aggregationproperties by the standard test described by Professor Born in Nature,194 927, (1962).

In this test, the ability of the above compounds to inhibit aggregationof blood platelets in 0.45 ml of human platelet rich plasma (PRP) wasmeasured. Aggregation was induced by the addition of any one ofarachidonic acid (AA), platelet activating factor (PAF) or collagen. PAFand its synthesis is disclosed by Hirth and Barner in Helv. Chim. Acta.Vol. 65; Fasc. 3, page 1059 (1982) [Compound 1-a on page 1061]. Bytitration of AA, collagen and PAF at various concentrations in 0.45 mlsamples of PRP, the minimum amount of AA, collagen and PAF whichproduces maximum blood platelet aggregation in a given sample of humanplatelet rich plasma (PRP) was determined. This minimum amount was usedwhen the compounds set forth above were tested for their ability toinhibit blood platelet aggregation in samples of PRP as described below.

In carrying out the tests, various concentrations of the test compoundwere added to separate samples of human platelet rich plasma (PRP). Toeach of these samples of PRP containing a specific concentration of oneof the above test compounds, there was added the minimum amount of AA,PAF, or collagen calculated above. The controls are samples of PRPcontaining no test compound but only the minimum amount of AA, PAF, orcollagen determined above. The percent aggregation of the varioussamples was determined by measuring the optical density of the samplesand comparing them with the optical density of the controls. Thisdetermination was made two minutes after the maximum first phaseresponse of PAF, AA or collagen. This determination was made withfreshly prepared samples of test compounds. A second determination wasmade in the same manner with samples of PRP two hours after the additionof AA, PAF or collagen. The IC₅₀, the dose at which the optical densityof the samples decrease to a value which is fifty (50%) percent of thevalue of the control was determined by the method disclosed by ProfessorBorn's article. The IC₅₀ values for the minimum dose were made fromconcentration response curve. These IC₅₀ 's were determined in twoseparate tests using PRP from two separate donors. The results of theminimum dose of each of the test compounds which reduces fifty (50%)percent of the aggregation of the platelets produced by any one of AA,PAF, or collagen is set forth in the following Table:

                  TABLE 1                                                         ______________________________________                                        Aggregation                                                                   IC.sub.50 (nm)                                                                Compound    AA          PAF    Collagen                                       ______________________________________                                        PGI.sub.2   0.45        0.15   2                                              Compound A  23          15     --                                             Compound B  20          6      6                                              ______________________________________                                    

The compounds of formulae I-A and I-B because of their potent bloodplatelet aggregation inhibiting activity are effective asanti-thrombotic agents and in treating disorders due to blood clotting.

The compounds of this invention possess the property of increasing thelevels of cyclic adenosine monophosphate (AMP) produced in bloodplatelets. Cyclic AMP prevents aggregation of blood platelets. Throughincreasing cyclic AMP, the compounds of this invention prevent bloodplatelet aggregation. That the compounds of this invention increasecyclic AMP can be seen from the following test.

In this test, human platelet rich plasma (PRP) was prepared bycentrifugation of blood treated with 0.38% by weight sodium citrate at180×g (times gravity) for ten minutes. The PRP (50 ml containingapproximately 2×10⁷ platelets) is incubated for two minutes at 22 C,with and without the test compound, in a Tris-HCl buffer for ten minutespH 7.4 containing 5.5 mM HCl, 1 mM Mg SO₄, 5 mM Na₂ H PO₄, 120 mM NaCl,and 5.5 mM glucose in a fluid volume of 250 ml. The reaction wasterminated by placing the samples in boiling water for 3 minutes. Theboiled extract was assayed for cyclic AMP by the protein binding methodof Brown et al. (Biochemical Journal 121:561-562, 1971). The activity ofthis test compound at 0.1 mM is measured as the percent increase incyclic AMP production compared to base 1 (vehicle alone) production. Theresults are given below:

    ______________________________________                                                     Cyclic AMP Production                                                         o/o stimulative of                                               Compound     Basal at 0.1 mM                                                  ______________________________________                                        PGI.sub.2    3721                                                             Compound A    998                                                             Compound B   1353                                                             ______________________________________                                    

The compounds of formulae I-A and I-B and their pharmaceuticallyacceptable salts because of their stability and their ability to inhibitblood platelet aggregation are effective in alleviating symptoms ofperiferal vascular diseases.

The compounds of formulae I-A and I-B or their pharmaceuticallyacceptable salts can be used in a variety of pharmaceuticalpreparations. In these preparations, these compounds or their salts areadministerable in the form of tablets, pills, powders, capsules,injectables, solutions, suppositories, emulsions, dispersions, and inother suitable forms. The pharmaceutical preparations which contain thecompounds of formulae I-A and I-B or their pharmaceutically acceptablesalts are conveniently formed by admixing them with a non-toxicpharmaceutical organic or inorganic carrier. Typical of pharmaceuticallyacceptable carriers are, for example, water, gelatin, lactose, starch,magnesium stearate, talc, vegetable oils, polyalkylene glycols,petroleum jelly and other conventionally employed pharmaceuticallyacceptable carriers. The pharmaceutical preparations may also containnon-toxic auxiliary substances such as emulsifying, preserving andwetting agents and the like, as for example, sorbitan monolaurate,triethanol amine oleate, polyoxyethylene sorbitan, dioctyl sodiumsulfosuccinate and the like.

The daily dose administered for the compounds will, of course, vary withthe particular novel compound employed because of the very potency ofthe compounds, the chosen route of administration and the size of therecipient. The dosage administered is not subject to definite bounds butit will usually be in effective amounts of the pharmacologicallyfunction of the prostacyclin. Representative of a typical method foradministering the prostacyclin compounds of formulae I-A and I-B orpharmaceutically acceptable salts thereof is by oral administration. Bythis route, the prostacyclins of formulae I-A and I-B or their salts canbe administered at a dosage of 0.1 micrograms to 0.50 milligrams per dayper kilogram of body weight.

The compounds of formula I-A and I-B and salts thereof and can beadministered to the skin in preparations for topical administrationssuch as solutions, suspensions, ointment, creams, gels, micronizedpowders, aerosols and the like. The pharmaceutical preparations may besterilized and/or may contain adjuvants such as preservatives,stabilizers, wetting agents, emulsifiers, salts for varying the osmoticpressure and/or buffers.

For topical administration to the skin the aforementioned compounds ortheir salts are preferably prepared as ointments, tinctures, creams,gels, solutions, lotions, sprays, suspensions, shampoos, hair soaps,perfumes and the like. In fact, any conventional composition utilizedfor application to the scalp or skin can be utilized in accordance withthis invention. Among the preferred methods of applying the compositioncontaining the agents of this invention is in the form of gel, lotionand cream solutions. The pharmaceutical preparation for topicaladministration to the skin can be prepared by mixing the aforementionedactive ingredient with non-toxic, therapeutically inert, solid or liquidcarriers customarily used in such preparations. These preparationsshould contain at least about 0.0005 percent by weight, of the activeingredient based upon the total weight of the composition. Since theactive ingredient, the compound of formula I, is non-toxic,non-teratogenic and non-irritating it may be used in topicalcompositions in amounts significantly exceeding 10 percent i.e. up to20% by weight. It is however preferred that these preparations containabout 0.01 to 10 percent by weight of the active ingredient based uponthe total weight of the composition. It is also preferred to apply thesepreparations once or twice daily to the skin. These preparations can beapplied according to the need of the patient. In carrying out thisinvention, the active ingredient can be applied in an aqueous solutionor an alcohol solution such as ethyl alcohol.

In preparing the topical preparations described above additives such aspreservatives, thickeners, perfumes, and the like conventional in theart of pharmaceutical compounding of topical preparations can be used.In addition, conventional antioxidants or mixtures of conventionalantioxidants can be incorporated into the topical preparationscontaining the aforementioned active agent. Among the conventionalantioxidants which can be utilized in these preparations are includedN-methyl-a-tocopherolamine, tocopherols, butylated hydroxyanisole,butylatedhydroxytoluene, ethoxyquin and the like. Cream-basepharmaceutical formulations containing the active agent, used inaccordance with this invention, are composed of aqueous emulsionscontaining a fatty acid alcohol, semi-solid petroleum hydrocarbon,1,2-ethyleneglycol and an emulsifying agent.

Ointment formulations containing the active agent in accordance withthis invention comprise admixtures of a semi-solid petroleum hydrocarbonwith a solvent dispersion of the active material. Cream compositionscontaining the active ingredient for use in this invention preferablycomprise emulsions formed from a water phase of a humectant, a viscositystabilizer and water, an oil phase of fatty acid alcohol, a semisolidpetroleum hydrocarbon and an emulsifying agent and a phase containingthe active agent dispersed in an aqueous stabilizer-buffer solution.Stabilizers may be added to the topical preparation. Any conventionalstabilizer can be utilized in accordance with this invention. In the oilphase, fatty acid alcohol components function as a stabilizer. Thesefatty acid alcohol components are derived from the reduction of along-chain saturated fatty acid of at least 14 carbon atoms. Also,conventional perfumes and lotions generally utilized in topicalpreparation for the hair can be utilized in accordance with thisinvention. Furthermore, if desired, conventional emulsifying agents canbe utilized in the topical preparations of this invention.

Among the preferred compound of formulae I-A and I-B are those compoundswhere the 7-fluoro substituent is in the beta configuration since thesecompounds are prepared easily in hibh yields. However, the compoundswhere the 7-fluoro substituted is in the alpha position are alsopreferred due to their enhanced stability. Among the 7-beta fluorocompounds, the following are preferred: ##STR3## where R is hydrogen orlower alkyl When R is lower alkyl in the compound of formulae I-Ai andI-Aii, R is preferably methyl or ethyl.

In preparing the compounds of this invention, the compound of formula IIis converted to a compound of the formula: ##STR4## wherein R₂, R₂ ', R₃and R₄ are as above; by hydrogenation utilizing conventionalhydrogenation catalysts such as palladium, rhodium and platinum. Incarrying out this reaction any of the conditions coventionally used incatalytic hydrogenation can be used. If desired, this reaction can becarried out with R₃ and R₄ being hydrogen. On the other hand, one orboth of the hydroxyl substituents on the compounds of formula II may beprotected with either an ether or an ester protecting group prior tobeing subjected to hydrogenation to produce the compounds of formulaIII. In the compound of formulae II and III, R₃ and R₄ can be anyconventional ether or ester protecting group such as the etherprotecting groups removable by acid catalyzed cleavage or the estergroups removable by hydrolysis.

In the next step in the production of the compounds of forula I-A andI-B, the compounds of formula III where R₃ and R₄ are other than atri(lower alkyl and/or aryl) silyl protecting group are converted tocompounds of the formula ##STR5## wherein R₂ and R₂ ' are as above; andR₅ is tri(lower alkyl and/or aryl)silyl;

Where R₃ and R₄ in the compound of III are hydrogen, the compound offormula III can be converted to the compound of formula III-B byreaction with a tri(lower alkyl and/or aryl) halosilane, preferablyt-butyl-dimethyl chlorosilane. Any of the conditions conventional inreacting a hydroxy compound with a halosilane to form a siloxyderivative can be used in carrying out this reaction. Where R₃ and R₄ inthe compound of formula III are a cleavable ether protecting group otherthan a tri(lower alkyl and/or aryl)silyl group, the protecting group canbe cleaved by procedures well known in the art to produce a compound ofthe formula III where R₃ and R₄ are hydrogen. On the other hand, whereR₃ and R₄ from a hydrolyzable ester groups, these groups can behydrolyzed by conventional means to form compounds of formula III whereR₃ and R₄ are hydrogen. These latter compounds can be converted to thecompound of formula III-B by reaction with a tri(lower alkyl and/oraryl)halosilane as described above.

The compounds of formulae I-A and I-B are prepared from the compound offormula III-B via the following intermediates: ##STR6## wherein R₂, R₂ 'and R₅ are as above; R₆ is lower alkyl and X is halogen; and R₇ istri(lower alkyl and/or aryl)silyl.

The compound of formula III-B is converted to the compound of formula Vby first enolizing the compound of formula III-B and then treating theenolized form of the compound of formula III-B with a tri(alkyl and/oraryl)halosilane. Any conventional method of enolizing can be utilized toenolize the compound of formula III-B. Among the preferred methods is bytreating the compound of formula III-B with a non-aqueous alkali metalbase. The preferred base for use in this reaction is lithium diisopropylamide or sodium hexamethyldisilazane. In carrying out the reactionutilizing the non-aqueous alkali metal base, temperatures of -70° C. to30° C. are generally preferred. Generally, this reaction is carried outin an inert organic solvent. Any conventional inert organic solventwhich is a liquid at the aforementioned temperatures can be utilized.Among the preferred solvents are tetrahydrofuran. The enolate of thecompound of formula III-B in the form of its alkali metal salt isconverted to the compound of formula V by treating with a tri(alkyland/or aryl)halosilane, preferably trimethylchlorosilane. Generally,this reaction is carried out at the same temperatures and in the samesolvent utilized to form the enolate.

The compound of formula V is converted to the compound of formula VI bytreating the compound of formula V with a fluorinating agent. Anyconventional fluorinating agent can be utilized in carrying out thisreaction. Among the preferred fluorinating agents is xenon difluoride.Generally, this reaction is carried out in the presence of an inertorganic solvent. Any conventional inert organic solvent can be utilizedin carrying out this reaction. Among the preferred solvents arehalogenated hydrocarbons such as methylene chloride, carbontetrachloride, etc. In carrying out this reaction, temperature andpressure are not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. While room temperature can beutilized, it is preferred to carry out this reaction at lowtemperatures, i.e. from -10° C. to +10° C.

In converting the compound of formula V to the compound of formula VI,the compound of formula VI is produced as a mixture of the followingcompounds: ##STR7## wherein R₂, R₂ ' and R₅ are as above.

The compounds of formulae VI-A and VI-B can be separated by conventionalmethods such as chromatography. On the other hand, the compound offormula VI as a mixture of the compounds of formulae VI-A and VI-B canbe utilized throughout the rest of the reactions or, if desired,separated at some later state in the reaction scheme to produce thecompound of formulae I-A or I-B having the desired fluoro orientation atthe 7-position. If the compound of formula VI is separated into thecompound of formulae VI-A and VI-B, the same configuration of thefluorine atom is carried out throughout the rest of the reactions toproduce the compounds of formula IA or IB. Therefore, in producing thecompounds of formulae I-A or I-B wherein the fluorine atom is at the7-beta position, the compound of formula VI-A is utilized in the rest ofthe reaction scheme to produce compounds of the formulae VIII throughXVI wherein the 7-fluoro substituent in these formulae is in the betaposition. If the compounds of I-A and I-B are desired wherein the fluorosubstituent is in the 7-alpha position, then the compound of formulaVI-B is utilized in the reaction scheme to produce the compounds offormulae VIII through XVI wherein the fluoro substituent shown in theseformulae is in the alpha position.

On the other hand, the compound of formula VI can be utilized withoutseparating into the compounds of formulae VI-A and VI-B. In this manner,the compounds of formulae I-A and I-B wherein the 7-fluoro substituentis in both the alpha and beta positions is produced via intermediates ofthe formulae VIII through XVI having the 7-fluoro group in bothpositions as shown.

The compound of formula VI is converted to the compound of formula VIIIby treating the compound of formula VI with a reducing agent. Incarrying out this reaction, any conventional reducing agent which willselectively reduce a lactone to a lactol can be utilized. Preferredreducing agents are the hydrides, particularly the aluminum hydridessuch as alkali metal aluminum hydride, and the borohydrides such asalkali metal borohydrides, with diisobutyl aluminum hydride beingparticularly preferred. Also, this reaction can be carried out utilizingdi(branched chain lower alkyl)boranes such asbis(3-methyl-2-butyl)borane. In carrying out this reaction, temperatureand pressure are not critical and the reaction can be carried out atroom temperature and atmospheric pressure or at elevated or reducedtemperatures and pressures. Generally, it is preferred to carry out thisreaction at a temperature of from -80° C. to room temperature. Thisreduction reaction can be carried out in the presence of an inertorganic solvent. Any of the conventional inert organic solvents can beutilized in carrying out this reaction. Among the preferred solvents aredimethoxy ethylene glycol, and the ethers such as tetrahydrofuran,diethyl ether and dioxane.

The compound of formula IX is obtained from the compound of formula VIIIby reaction the compound of formula VIII with phosphonium salts of theformula: ##STR8## wherein R₁₅, R₁₅ ', R₁₅ " is aryl or di(loweralkyl)-amino; and Y is halogen via a conventional Wittig type reaction.Any of the conventional conditions in Wittig reactions can be utilizedin carrying out this reaction.

The compound of formula IX can be converted to a compound of the formulaX by esterification with diazomethane or a reactive derivative of alower alkanol such as a lower alkyl halide. Any conventional conditionsutilizing in these esterifying reactions can be utilized to form thecompound of formula X from the compound of formula IX.

The compound of formula X is converted to the compound of formula XI bytreating the compound of formula X with a halogenating agent. Among thepreferred halogenating agents are included N-halosuccinimides,particularly N-iodosuccinimide. Generally, this reaction is carried outin the presence of a polar solvent such as acetonitrile and halogenatedhydrocarbons such as methylene chloride, ethylene chloride, etc. Infact, any conventional polar organic solvent can be utilized. Incarrying out this reaction, temperatures of from 0° C. to 35° C. can beutilized. Generally, it is preferred to carry out this reaction at roomtemperature.

The compound of formula XI is converted to the compound of formula XIIby ether cleavage. Any conventional method of ether cleavage describedhereinbefore can be utilized to carry out this reaction.

In the next step, the compound of formula XII is treated with adehydrohalogenating agent to produce the compounds of formulae XIII andXIV in admixture. In carrying out this reaction, any conventionaldehydrohalogenating agent can be utilized. Among the preferreddehydrohalogenating agents are the diazabicycloalkanes or alkanes suchas 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane.Furthermore, any other conventional organic base utilized fordehydrohalogenation can be utilized in carrying out this reaction. Thisreaction produces the compounds of formula XIII and the compounds offormula XIV in admixture. The compounds of formula XIII can be separatedfrom the compounds of formula XIV by any conventional separationprocedure such as chromatography.

The compound of formula XIII can be converted to the compound of formulaXV and the compound of formula XIV is converted to the compound offormula XVI by hydrolysis. Any conventional method of ester hydrolysiscan be utilized in carrying out these reactions. Among the preferredmethod of ester hydrolysis is either treating the compound of formulaXIII or the compound of formula XIV with a alkali metal hydroxide. Amongthe preferred alkali metal hydroxides for use in this reaction aresodium and potassium hydroxides.

In the practice of this invention, any pharmaceutically acceptable basicsalts of the compound of formula I-A and I-B where R is hydrogen can beutilized. Among the preferred pharmaceutically acceptable basic saltsare included the alkali metal salts such as lithium, sodium, andpotassium, with sodium being especially preferred. Other salts which arealso preferred are the alkaline earth metal salts such as calcium andmagnesium, amine salts such as the lower alkyl amines, e.g. ethylamineand the hydroxysubstituted lower alkyl amine salts andtris(hydroxymethyl)aminomethane. Also preferred are the ammonium salts.Among the other salts are dibenzylamine, monoalkylamines or dialkylamineand salts with amino acids (i.e. salts with arginine and glycine).

The following Examples are illustrative but not limitative of theinvention. In the Examples, the ether utilized was diethyl ether. Alltemperatures are in degrees Centigrade. Celite is diatomaceous earth andDMF is dimethyl formamide.

EXAMPLE 1 [3aR-[3a alpha,4alpha(3S*),5beta,6aalpha]]-5-(Benzoyloxy)Hexahydro-4-(3-Hydroxyoctyl)-2H-Cyclopenta[b]furan-2-one

To 2 g of platinum in 100 ml of ethyl acetate was added a solution of19.8 g (0.053 mol) of [3aR-[3a alpha,4alpha-(1E,3S*),5beta,6aalpha]]-5-(benzoyloxy)hexahydro-4-(3-hydroxy-1-octenyl)-2H-cyclopenta[b]furan-2-onein 100 ml of ethyl acetate. The solution was then hydrogenated until thetheoretical uptake of hydrogen was complete (ca. 2h) and then filteredthrough a bed of Celite. The solvent was then removed under reducedpressure to give 19.9 g. of [3aR-[3a alpha,4alpha(3S*),5beta,6aalpha)]-5-(benzoyloxy)hexahydro-4-(3-hydroxyoctyl)-2H-cyclopenta[b]furan-2-oneas colorless oil (100% yield) [α]_(D) ²⁵ -72.03 (CHCl₃, C=0.794).

Anal. Calcd for C₂₂ H₃₀ O₅ : C, 70.56, H, 8.80. Found: C, 70.51; H,7.97.

EXAMPLE 2 [3aR-[3a alpha,4alpha(3R*,4S*),5beta,6aalpha]]-5-(Benzoyloxy)-4-(4-Fluoro-3-Hydroxyoctyl)Hexahydro-2H-Cyclopenta[b]furan-2-one

To 1.1 g of platinium in 50 ml of ethyl acetate was added a solution of11 g (0.028 mol) of [3aR-[3a alpha,4alpha(1E,3R*,4S*),5beta,6aalpha]]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxy-1-octenyl)hexahydro-2H-cyclopenta[b]furan-2-onein 110 ml of ethyl acetate. The mixture was then hydrogenated until thetheoretical uptake of hydrogen was complete and then filtered through abed of Celite. The solvent was then removed under reduced pressure andthe residue chromatographed over 250 g of silica gel (toluene --α 30% byvolume ethyl acetate/70% by volume toluene) to afford 10.7 g of [3aR-[3aalpha,4alpha(3R*,4S*),5beta,6aalpha)]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxyoctyl)hexahydro-2H-cyclopenta[b]furan-2-one(94% yield) as a colorless oil.

Anal. Calcd for C₂₂ H₂₉ FO₅ : C, 67.33; H, 7.45. Found: C, 66.80; H,7.51.

EXAMPLE 3 [3aR-[3a alpha,4alpha(3S*),5beta,6aalpha]]-Hexahydro-5-[[(1,1-Dimethylethyl)Dimethylsilyl]oxy]-4-[3-[[(1,1-Dimethylethyl)Dimethylsilyloxy]octyl]-2H-Cyclopenta[b]furan-2-one

To a solution of 20.5 g (0.055 mol) of [3aR-[3aalpha,4alpha-(3S*),5beta,6aalpha]]-5-(benzoyloxy)hexahydro-4-(3-hydroxyoctyl)-2H-cyclopenta-[b]furan-2-onedissolved in 200 ml of methanol was added 14.35 g of Na₂ CO₃. After 4 hran additional 14.4 g of Na₂ CO₃, was added and then again 3 hr later.The mixture was then filtered and the Na₂ CO₃, washed with dry methanol.The methanol was removed under reduced pressure and the residuedissolved in ethyl acetate. The ethyl acetate solution was washed withwater; the water layer saturated with NaCl and extracted with additionalethyl acetate. The ethyl acetate solutions were combined and dried(MgSO₄). The solvent was then removed under reduced pressure and theresidue chromatographed on 400 g of silica gel (5% by volume ethylacetate/95% by volume hexane --α ethyl acetate) to give 11 g of thediol, i.e. 3aR-[3a alpha,4alpha(3S*),5beta,6aalpha]]-5-hydroxy-4-(3-hydroxyoctyl)-2H-cyclopenta[b]furan-2-one.

To 10.2 g of the diol dissolved in 150 ml of DMF was added 13.1 g ofimidazole followed by 23.4 g of t-butyldimethylchlorosilane and thereaction mixture stirred for 18 hr. The mixture was then added to 500 mlof 0.5N NH₄ Cl solution and the mixture extracted with 3×500 ml ofether. The combined ether extracts were washed with a saturated NaHCO₃solution followed by a saturated NaCl solution. The ether solution wasthen dried (MgSO₄), the ether removed under reduced pressure and theresidue chromatographed on 500 g of silica gel (10% by volume ether/90%by volume petroleum ether --α 20% by volume ether/80% by volumepetroleum ether) to give 13.6 g of [3aR-[3a alpha,4alpha(3S*),5beta, 6aalpha]]hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl]-2H-cyclopenta[b]furan-2-oneas a colorless oil.

Anal. Calcd for C₂₇ H₅₄ O₄ Si₂ : C, 65.00; H, 10.91. Found: C, 64.84; H,11.03.

EXAMPLE 4 [3aR-[3a alpha,4alpha(3R*,4S*),5beta,6aalpha]]-Hexahydro-4-(4-fluoro-3-hydroxyoctyl)-5-hydroxy-2H-cyclopenta[6]furan-2-one

To a solution of 10.3 g (0.026 mol) of [3aR-[3aalpha,4alpha(3R*,4S*),5beta,6aalpha]]-hexahydro-5-(benzoyloxy)-4-(4-fluoro-3-hydroxyoctyl)2H-cyclopenta[b]furan-2-onedissolved in 200 ml of CH₃ OH was added 7 g of Na₂ CO₃, After severalhours an additional 5 g of Na₂ CO₃ was added and the mixture allowed tostir overnight. The mixture was filtered and the solvent removed underreduced pressure. The residue was dissolved in CH₂ Cl₂, dried (MgSO₄),and the solvent removed under reduced pressure. The resulting solid wasthen triturated with a small amount of cold ether to give 5.5 g (73.3%yield) of [3aR-[3a alpha,4alpha(3R*,4S*), 5beta,6aalpha]]-hexahydro-4-(4-fluoro-3-hydroxyoctyl)-5-hydroxy-2H-cyclopenta[b]furan-2-oneas white crystals: mp 99°-100° C.; [a]_(D) ²⁵ -18.86 (CHCl₃, C=1.0).

Anal. Calcd for C₁₅ H₂₅ FO₄ : 6, 62.48; H, 8.74. Found: C, 62.48: H,8.67.

EXAMPLE 5 [3aR-[3a alpha, 4alpha(3R*,4S*),5beta,6aalpha]]Hexahydro-5-[[(1,1-Dimethylethyl)Dimethylsilyl]oxy]-4-[[[3-(1,1-Dimethylethyl)Dimethylsilyl]oxy]-4-Fluorooctyl]-2H-Cyclopenta[b]furan-2-one

To a solution of 6.0 g (0.0208 mol) of [3aR-[3a alpha, 4alpha(3R*,4S*),5beta,6aalpha]]-hexahydro-4-(4-fluoro-3-hydroxy-octyl)-5-hydroxy-2H-cyclopenta[b)furan-2-onedissolved in 100 ml of dry DMF was added 7.2 g of imidazole and 12.9 gof t-butyldimethylchlorosilane. After 18 hr the reaction mixture waspoured into 500 ml of 0.5N cold (0° C.) HCl and the mixture extractedwith ether. The ether extract was washed with a saturated NaHCO₃,solution followed by a saturated NaCl solution. The ether solution wasthen dried and the solvent removed under reduced pressure.Chromatography on silica gel (2% by volume ethyl acetate/98% by volumehexane --α 20% by volume ethyl acetate/80% by volume hexane) afforded9.5 g (85.4% yield) of [3aR-[3a alpha, 4alpha(3R*,4S*),5beta,6aalpha]]-hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluorooctyl]-2H-cyclopenta[b]furan-2-one;[α]_(D) ²⁵ -30.13 (CHCl₃,C=1.08).

Anal. Calcd for C₂₇ H₅₃ FO₄ Si₂ : C, 62.74; H, 10.34. Found: C, 62.88;H, 10.56.

EXAMPLE 6 [3S-[3alpha,3a alpha,4alpha(3S*),5beta,6aalpha]]-3-Hexahydro-3-fluoro-5-[[(1,1-Dimethylethyl)Dimethylsilyl]oxy]-4-[3-[[(1.1-Dimethylethyl)dimethylsilyl]oxy]octyl]-2H-Cyclopenta[b]furan-2-one

To a solution of 4.5 ml of diisopropylamine in 50 ml of dry THF(tetrahydrofuran) cooled to 0° C. was added dropwise over a period oftwenty minutes 19.6 ml of n-butyllithium (1.5M in hexane). Afterstirring an additional five minutes at 0° C. the solution was cooled to-40° C. (dry ice/acetone) after which time a solution of 13.1 g (0.0263mol) of [3aR-[3a alpha,4alpha(3S*), 5beta,6aalpha]]-hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl)-2H-cyclopenta[b]furan-2-onedissolved in 100 ml of THF was added slowly while maintaining thetemperature at -40° C. After five minutes at this temperature 4.5 ml oftrimethylchlorosilane was added rapidly. The cooling bath was thenremoved and the reaction allowed to warm to 15 C. The solvent was thenremoved under vacuum and the residue treated with 50 ml of dry ether.The mixture was then filtered through a cintered glass filter and thesolvent evaporated under high vacuum to produce [3aR-[3a alpha, 4alpha(3S*), 5 beta, 6aalpha]]-4,5,6,6a-tetrahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[1,1-dimethylethyl)dimethylsilyl]oxy]-octyl]-2-[(trimethylsilyl)oxy]-3aH-cyclopenta[b]furan.This compound was then dissolved at 0° C. in 50 ml of dry CH₂ Cl₂containing 5.26 g of KHCO₃, followed by the slow addition of 5.0 g ofxenon difluoride. The mixture was then stirred for an additional 0.5 hrat 0° C. and then poured into 500 ml of ice water followed by extractionwith CH₂ Cl₂. The organic layer was separated, dried, and the solventremoved under reduced pressure. The residue (9.1 g) was thenchromatographed on 500 g of silica gel (2% by volume ethyl acetate/98%by volume petroleum ether to 10% ethyl acetate/90% by volume petroleumether) and afforded 2.2 g of starting material and 7 g (51.5% yield) of[3S-[3alpha,3a alpha,4alpha(3S*),5beta,6aalpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl]-2H-cyclopenta[b]furan-2-oneas a colorless liquid [α]_(D) ²⁵ -29.35 (CHCl₃, C=0.726).

Anal. Calcd for C₂₇ H₅₃ FO₄ Si₂ : C, 62.74; H, 10.34. Found: C, 62.94;H, 10.16.

EXAMPLE 7 [3S-[3alpha,3a alpha,4alpha(3R*,4S*),5beta,6aalpha]]-Hexahydro-3-Fluoro-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-Fluorooctyl]-2H-Cyclopenta[b]furan-2-one

To a solution of 4.4 g of lithium hexamethyldisilazide in 100 ml of dryTHF under argon at -70° C. was added dropwise to a solution of 9.0 g(0.0174 mol) of [3aR-[3a alpha,4alpha (3R*,4S*),5beta,6aalpha]]-hexahydro-5-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]-oxy]-4-fluorooctyl]-2H-cyclopenta[b]furan-2-onedissolved in 100 ml of dry THF. After stirring for thirty minutes at-70° C. the temperature was allowed to rise to -45° C. at which time 3.8ml of trimethylchlorosilane was added over a five-minute period. Thecooling bath was then removed and the reaction mixture slowly warmed toroom temperature. The THF was then removed under high vacuum to produce[3aR-[3a alpha, 4alpha (3R*,4S*),5beta, 6aalpha]]-4,5,6,6a-tetrahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)-dimethylsilyl]oxy]-4-fluorooctyl]-3aH-cyclopenta[b]furanas a residue. This residue was dissolved in 100 ml of dry CH₂ Cl₂ at 0°C. To the solution was then added 3.5 g KHCO₃, followed by the slowaddition of 3.2 g of xenon difluoride. At the completion of theaddition, the reaction mixture was stirred for an additional ten minutesand then poured into a mixture of 250 ml of saturated NaHCO₃, containing1 g of Na₂ S₂ O₃.5H₂ O and 500 ml of ether. The aqueous layer wasseparated and extracted with ether. The ether solutions were combined,washed with a saturated NaCl solution, dried (MgSO₄) and the solventremoved under reduced pressure. The residue was then chromatographed on250 g of silica gel (2% by volume ethyl acetate/98% by volume hexane to3% by volume ethyl acetate/97% by volume hexane) to give 6.2 g (66.7%yield) of [3S-[3alpha,3a alpha,4alpha(3R*,4S*),-5beta,6aalpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)-dimethylsilyl]-oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluorooctyl]-2H-cyclopenta[b]furan-2-oneas a colorless oil. [α]_(D) ²⁵ -37.38 (CHCl₃, C=0.7).

Anal. Calcd for C₂₇ H₅₂ F₂ O₄ Si₂ : C, 60.63; H, 9.80. Found: C, 60.41;H, 9.60.

EXAMPLE 8 [3S-[3alpha,3a alpha,4alpha(3S*),5beta,6aalpha]]-Hexahydro-3-Fluoro-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]octyl]-2H-Cyclopenta[b]furan-2-ol

To a solution of 7.3 g (0.0141 mol) of [3S-[3alpha,3aalpha,4alpha-(3S*),5beta,6aalpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl]-2H-cyclopenta[b]furan-2-onecooled to -70° C. was added dropwise 14 ml of diisobutylaluminum hydride(25 wt. %, 1.5M) in toluene. The solution was allowed to stir anadditional twenty minutes at -70° C. after which time 20 ml of asaturated NH₄ Cl solution was added slowly. The mixture was then warmedto 15° C. diluted with 200 ml of ethyl acetate and washed with asaturated NaCl solution. The washings were extracted with ethyl acetate.The ethyl acetate solutions were combined and dried (MgSO₄). Removal ofthe solvent under reduced pressure afforded 7.2 g of residue which waschromatographed over 500 g of silica gel (10% by volume ethylacetate/90% by volume petroleum ether) to give 6.3 g (86.1% yield) of[3S-[3alpha, 3a alpha,4alpha(3S*),5beta,6aalpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl]-2H-cyclopenta[b]furan-2-olas a colorless oil. [α]_(D) ²⁵ -17.27 (CHCl₃, C=0.956).

Anal. Calcd for C₂₇ H₅₅ FO₄ Si₂ : C, 62.50; H, 10.68. Found: C, 62.16;H, 10.62.

EXAMPLE 9 [3S-[3alpha,3a alpha,4alpha(3R*,4S*),5beta,6aalpha]]-Hexahydro-3-Fluoro-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-Fluorooctyl]-2H-Cyclopenta[b]furan-2-ol

By the procedure of example 8, [3S-[3alpha,3a alpha, 4alpha(3R*,4S*),5beta,6aalpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluorooctyl]-2H-cyclopenta[b]-furan-2-one6.2 g (0.0116 mol) was converted to 6 g (80.6% yield) of [3S-[3alpha,3aalpha,4alpha(3R*,4S*),5beta,6aalpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluorooctyl]-2H-cyclopenta[b]furan-2-olobtained as a colorless oil [α]_(D) ²⁵ -27.38 (CHCl₃, C=0.913).

Anal. Calcd for C₂₇ H₅₄ F₂ O₄ Si₂ : C, 60.40; H, 10.14. Found: C, 60.35;H, 9.99.

EXAMPLE 10(5R,6R,7beta,9alpha,11alpha,15S)-6,9-Epoxy-7-Fluoro-11,15-Dihydroxy-5-Iodo-ProstanoicAcid Methyl Ester and(5S,6S,7beta,9alpha,11alpha,15S)-6,9-Epoxy-7-Fluoro-11,15-Dihydroxy-5-Iodo-prostanoicAcid Methyl Ester

To a mixture of 15 g (0.0338 mol) of(4-carboxybutyl)triphenylphosphonium bromide (dried under high vacuum at100° C. for 18 hr) and 13.5 g (0.0736 mol) of sodiumhexamethyldi-silazane under argon was added 200 ml of dry THF followedby 13.4 ml of freshly distilled hexamethylphosphoramide. The resultingorange-red suspension was stirred at room temperature for 1 hr. To thismixture was then added 6.3 g (0.0122 mol) of [3S-[3alpha,3a alpha,4alpha(3S*),5beta,6aalpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl]-2H-cyclopenta[b]furan-2-oldissolved in 100 ml of dry THF. The resulting yellow-orange mixture wasallowed to stir overnight after which time glacial acetic acid was addeddropwise until the mixture became colorless. The mixture was thenpartitioned between 500 ml of ether and 300 ml of H₂ O at 0° C. and thentreated with 1N HCl to pH 3. The layers were separated and the waterwashed with a saturated NaCl solution and dried (MgSO₄).

The ether was then removed under reduced pressure to give 15 g of alight yellow oil containing (5Z,7R,9alpha,11alpha,15S)-7-fluoro-11,13-bis-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]prost-5-en-1-oicacid. The crude acid was then taken up in 50 ml of dry CH₂ Cl₂ andtreated with an ethereal solution of diazomethane. The excessdiazomethane was blown off with a stream of argon. The residue was takenup in ether, dried (MgSO₄), and the solvent removed under reducedpressure. Chromatography over 500 g silica gel (2% ethyl acetate/98% byvolume petroleum ether to 20% ethyl acetate/80% by volume petroleumether) afforded 5 g of(5Z,7R,9alpha,11alpha,15S)-7-fluoro-11,15-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]prost-5-en-1-oicacid methyl ester.

To a solution of 6.0 g of the methyl ester prepared above in 120 ml ofdry acetonitrile was added 16.5 g of N-iodosuccinimide and the resultingmixture stirred 18 hr at room temperature in the absence of light. Themixture was then treated with 500 ml of ether and the resulting solutionwashed with a 10% by weight aqueous solution of Na₂ S₂ O₃. The washingswere back extracted with ether. The ether solutions were combined anddried (MgSO₄). The solvent was then removed under reduced pressure toproduce a mixture of(5R,6R,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy)-5-iodo-prostanoicacid methyl ester and(5S,6S,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-iodo-prostanoicacid methyl ester as a residue. This residue was then treated with amixture of 60 ml of THF, 120 ml of glacial acetic acid and 60 ml ofwater. The mixture was warmed to 50° C. for 18 hr and the solventremoved under high vacuum. The residue, 6.7 g was then chromatographedover 500 g. of silica gel (ether to 50% by volume ether/50% by volumeethyl acetate) to afford 2.9 g of a mixture of(5R,6R,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-dihydroxy-5-iodo-prostanoicacid methyl ester and(5S,6S,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,16-dihydroxy-5-iodo-prostanoicacid methyl ester.

Anal. Calcd for C₂₁ H₃₆ FIO₅ : C, 49.03; H, 7.05. Found: C, 49.36; H,7.04.

EXAMPLE 11 A mixture of[5S,6S,7beta,9alpha,11alpha,15R,16S]-6,9-Epoxy-7,16-Difluoro-11,15-Dihydroxy-5-Iodo-prostanoicAcid Methyl Ester; and(5R,6R,7beta,9alpha,11alpha,15R,16S)6,9-Epoxy-7,16-Difluoro-11,15-Dihydroxy-5-Iodo-prostanoicAcid Methyl Ester

By the procedure of Example 10, [3S-[3alpha,3aalpha,4alpha(3R*,4S*),5beta,6aalpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)-dimethylsilyl]oxy]-4-fluorooctyl]-2H-cyclopenta[b)furan-2-ol4.6 g (0.0086 mol) was converted to 2 g of a mixture of(5S,6S,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-5-iodo-prostanoicacid methyl ester and(5R,6R,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-5-iodo-prostanoicacid methyl ester via the following intermediates:

(5Z,7R,9alpha,11alpha,15R,16S)-7,16-difluoro-11,15-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-prosta-5-en-1-oicacid,

(5Z,7R,9alpha,11alpha,15R,16S)-7,16-difluoro-11,15-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-prosta-5-en-1-oicacid methyl ester; and

A mixture of(5R,6R,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-bis[[(1,1-dimethyl-ethyl)dimethylsilyl]oxy]-5-iodo-prostanoicacid methyl ester; and(5S,6S,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy-prosta-5-en-1-oicacid methyl ester.

EXAMPLE 12

From the mixture produced in Example 11, pure[5S,6S,7beta,9alpha,11alpha,15R,16S]-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-5-iodo-prostanoicacid methyl ester was isolated. [α]_(D) ²⁵ +14.08 (CHCl₃, C=0.15).

Anal. Calcd for C₂₁ H₃₅ F₂ IO₅ : C, 47.38; H, 6.63; Found: C, 46.81; H6.84.

EXAMPLE 13(5Z,7beta,9alpha,11alpha,15S)-6,9-Epoxy-7-Fluoro-11,15-DiHydroxy-Prost-5-en-1-oicAcid Methyl Ester and(4E,7beta,9alpha,11alpha,15S)-6,9-Epoxy-7-Fluoro-11,15-Dihydroxy-Prost-4-en-1-oicAcid Methyl Ester

To a solution of 2.8 g (0.0054 mol) of(5R,6R,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-dihydroxy-5-iodo-prostanoicacid methyl ester and(5S,6S,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-dihydroxy-5-iodoprostanoicacid methyl ester dissolved in 200 ml of dry toluene was added 5.04 mlof 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The solution was thenheated under argon at 90° C. for 45 hr. The reaction was then cooled,added to 200 ml of ice water and extracted with 3×250 ml of ether. Theether solutions were combined, washed with a saturated solution of NaCland dried (MgSO₄). The ether was removed under vacuum and the residue(1.9 g) chromatographed over 250 g of silica gel. Elution with 50% byvolume ethyl acetate/50% by volume petroleum ether to 75% by volumeethyl acetate/25% by volume petroleum ether afforded 1.2 g of(5Z,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-dihydroxy-prost-5-en-1-oicacid methyl ester as a light yellow oil. [α]_(D) ²⁵ +59.53 (CHCl₃,C=0.719).

Anal. Calcd for C₂₁ H₃₅ FO₅ : C, 65.26; H, 9.12. Found: C, 64.73; H,8.95.

Continued elution of the column with 100% by volume of ethyl acetateafforded 0.456 g of(4E,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-dihydroxy-prost-4-en-1-oicacid methyl ester as a light yellow oil.

Anal. Calcd for C₂₁ H₃₅ FO₅ : C, 65.26; H, 9.12. Found: C, 64.68; H,9.13.

EXAMPLE 14(5Z,7beta,9alpha,11alpha,15R,16S)-6,9-Epoxy-7,16-Difluoro-11,15-Dihydroxy-Prost-5-en-1-oicAcid Methyl Ester and(4E,7beta,9alpha,11alpha,15R,16S)-6,9-Epoxy-7,16-Difluoro-11,15-Dihydroxy-prost-4-en-1-oicAcid Methyl Ester

A solution of 2 g of a mixture of(5S,6S,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-5-iodo-prostanoicacid methyl ester and(5R,6R,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-5-iodo-prostanoicacid methyl ester and 20 ml of DBU was allowed to stir under anatmosphere of argon for 20 hr. The mixture was then poured into 200 mlof ice water and extracted with ethyl acetate. The ethyl acetatesolution was then washed with a saturated NaCl solution and dried(MgSO₄). The solvent was then removed under reduced pressure to give 1.7g of crude product which was chromatographed on 250 grams of silica gel.Elution with 50% by volume ethyl acetate/50% by volume petroleum etherto 75% by volume ethyl acetate and 25% by volume petroleum etherafforded 0.806 g of (5Z,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-prost-5-en-1-oic-acid methyl esteras a colorless liquid. [α]_(D) ²⁵ +52.85 (CHCl₃, C=0.42).

Anal. Calcd for C₂₁ H₃₄ F₂ O₅ : C, 62.36: H, 8.47. Found: C, 62.04; H,8.46.

Continued elution with 75% by volume ethyl acetate/25% by volumepetroleum ether then afforded 0.497 g of(4E,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-prost-4-en-1-oicacid methyl ester as a colorless oil. [α]_(D) ²⁵ +32.35 (CHCl₃, C=0.22).

Anal. Calcd for C₂₁ H₃₄ F₂ O₅ : C, 62.36; H, 8.47. Found: C, 61.73; H,8.61.

EXAMPLE 15(5Z,7beta,9alpha,11alpha,15R,16S)-6,9-Epoxy-7,16-Difluoro-11,15-Dihydroxy-Prost-5-en-1-oicAcid Sodium Salt

To a solution of 53.3 mg (0.00013 mol) of(5Z,7beta,9alpha,11alpha,15R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-prost--en-1-oicacid methyl ester in 1 ml of CH₃ OH, 1 ml of THF and 1 ml H₂ O under anatmosphere of argon was added 0.131 ml of 1N NaOH. The reaction mixturewas allowed to stir at room temperature for 18 hr and the solvent thenremoved under high vacuum. The residue was then dissolved in 1 ml ofethyl acetate followed by eight drops of methanol. The mixture was thenfiltered and the residue washed with a solution of eight drops ofmethanol in 1 ml of ethyl acetate. To the combined ethyl acetatesolutions was added 10 ml of hexane and the mixture allowed to remain inthe refrigerator for 18 hr. The solvent was then decanted from the oilyresidue, and the residue then washed with 10 ml of petroleum ether. Theresidue was then subjected to high vacuum after which it was dissolvedin 4 ml of water and lypolized. The resulting solid was then trituratedwith hexane and dried under vacuum to give 48 mg of(5Z,7beta,9alpha,11alpha,115R,16S)-6,9-epoxy-7,16-difluoro-11,15-dihydroxy-prost--en-1-oicacid sodium salt as a white crystalline solid.

Anal. Calcd for C₂₀ H₃₁ F₂ NaO₅ : C, 58.24; H, 7.58; F, 9.21. Found: C,57.54; H, 7.44; F, 9.88.

EXAMPLE 16(5Z,7beta,9alpha,11alpha,15S)-6,9-Epoxy-7-Fluoro-11,15-Dihydroxyprost-5-en-1-oicAcid Monosodium Monohydrate

By the procedure of Example 15, 50 mg of(5Z,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,15-dihydroxyprost-5-en-1-oicacid methyl ester was converted to 26 mg of(5Z,7beta,9alpha,11alpha,15S)-6,9-epoxy-7-fluoro-11,16-dihydroxyprost-5-en-1-oicacid monosodium salt monohydrate (obtained as a white solid).

Anal. Calcd for C₂₀ H₃₂ F₂ NaO₅.H₂ O: C, 58.24; H, 8.31; F. 4.61. Found:C, 58.04; H, 8.43; F, 4.45.

EXAMPLE 17

    ______________________________________                                        CAPSULE FORMULATION                                                           Ingredient      mg/cap                                                        ______________________________________                                        1.  [5Z,7beta,9alpha,                                                                             0.01    0.5   5.0   25.0                                      11alpha,15R,16S] -                                                            6,9-epoxy-7,16-di-                                                            fluoro-11,15-dihydroxy                                                        prosten-5-en-1-oic acid                                                       sodium salt                                                               2.  Lactose Hydrose 168.99  168.5 159.0 123.0                                 3.  Corn Starch     20.0    20.0  25.0  35.0                                  4.  Talc            10.0    10.0  10.0  15.0                                  5.  Mg stearate     1.0     1.0   1.0   2.0                                                       200.0   200.0 200.0 200.0                                 ______________________________________                                    

Manufacturing Procedure

1. Mix items 1, 2, and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill in suitable capsule.

EXAMPLE 18

    ______________________________________                                        CAPSULE FORMULATION                                                           Ingredient    mg/cap                                                          ______________________________________                                        1.  (5Z,7beta,9alpha,                                                                           0.01    0.5     5.0   25.0                                      11alpha,15R,16S)-                                                             6,9-epoxy-7-fluoro-                                                           11,15-dihydroxy                                                               prost-5-en-1-oic acid                                                         methyl ester                                                              2.  Lactose Hydrose                                                                             168.99  168.5   159.0 123.0                                 3.  Corn Starch   20.0    20.0    25.0  35.0                                  4.  Talc          10.0    10.0    10.0  15.0                                  5.  Mg stearate   1.0     1.0     1.0   2.0                                                     200.0   200.0   200.0 200.0                                 ______________________________________                                    

Manufacturing Procedure

1. Mix items 1, 2, and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill in suitable capsule.

EXAMPLE 19

    ______________________________________                                        CAPSULE FORMULATION                                                           Ingredient       mg/cap                                                       ______________________________________                                        1.  (5Z,7beta,9alpha,                                                                              0.01    0.5   5.0   25.0                                     11alpha,15R,16S)-                                                             6,9-epoxy-7,16-difluoro-                                                      11,15-dihydroxy                                                               prost-5-en-1-oic acid                                                         methyl ester                                                              2.  Lactose Hydrose  168.99  168.5 159.0 123.0                                3.  Corn Starch      20.0    20.0  25.0  35.0                                 4.  Talc             10.0    10.0  10.0  15.0                                 5.  Mg stearate      1.0     1.0   1.0   2.0                                                       200.0   200.0 200.0 200.0                                ______________________________________                                    

Manufacturing Procedure

1. Mix items 1, 2, and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill in suitable capsule.

EXAMPLE 20

    ______________________________________                                        SOFT GELATIN CAPSULE FORMULATION                                              Ingredient      mg/cap                                                        ______________________________________                                        1.  [5Z,7beta,9alpha,                                                                             0.01    0.5   5.0   25.0                                      11alpha,15R,16S]-                                                             6,9-epoxy-7,16-di-                                                            fluoro-11,15-dihydroxy                                                        prosten-5-en-1-oic acid                                                       sodium salt                                                               2.  PEG 400         149.49  149.0 194.5 374.5                                     (Polyethylene                                                                 glycol molecule                                                               at 400)                                                                   3.  Ascorbyl Palmitate                                                                            0.5     0.5   0.5   0.5                                                       150.0   150.0 200.0 400.0                                 ______________________________________                                    

Manufacturing Procedure

1. Dissolve item 3 in item 2.

2. Add item 1 to the solution in Step 1 and mix until dissolved.

3. Fill in soft gelatin capsule.

EXAMPLE 21

    ______________________________________                                        CAPSULE FORMULATION                                                           Ingredient       mg/cap                                                       ______________________________________                                        1.  (5Z,7beta,9alpha,                                                                              0.01    0.5   5.0   25.0                                     11alpha,15R,16S)-                                                             6,9-epoxy-7,16-difluoro-                                                      11,15-dihydroxy                                                               prost-5-en-1-oic acid                                                         methyl ester                                                              2.  PEG 400          149.49  149.0 194.5 374.5                                3.  Ascorbyl Palmitate                                                                             0.5     0.5   0.5   0.5                                                       150.0   150.0 200.0 400.0                                ______________________________________                                    

Manufacturing Procedure

1. Dissolve item 3 in item 2.

2. Add item 1 to the solution in Step 1 and mix until dissolved.

3. Fill in soft gelatin capsule.

EXAMPLE 22

    ______________________________________                                        WET GRANULATION FORMULATION                                                   Ingredient      mg/cap                                                        ______________________________________                                        1.  [5Z,7beta,9alpha,                                                                             0.01    0.5   5.0   25.0                                      11alpha,15R,16S]-                                                             6,9-epoxy-7,16-di-                                                            fluoro-11,15-dihydroxy                                                        prosten-5-en-1-oic acid                                                       sodium salt                                                               2.  Lactose anhydrose                                                                             106.99  106.5 102.0 118.0                                     DTG                                                                       3.  Avicel pH 102   15.0    15.0  15.0  25.0                                      (microcrystalline                                                             cellulose)                                                                4.  Modified Starch 7.0     7.0   7.0   10.0                                  5.  Magnesium stearate                                                                            1.0     1.0   1.0   2.0                                                       130.0   130.0 130.0 130.0                                 ______________________________________                                    

Manufacturing Procedure

1. Dissolve item 1 in a suitable solvent such as alcohol.

2. Spread the solution in Step 1 over item 2, dry.

3. Add items 3 and 4 and mix for 10 minutes.

4. Add magnesium stearate and mix for 3 minutes and compress.

EXAMPLE 23

    ______________________________________                                        WET GRANULATION FORMULATION                                                   Ingredient       mg/cap                                                       ______________________________________                                        1.  (5Z,7beta,9alpha,                                                                              0.01    0.5   5.0   25.0                                     11alpha,15R,16S)-                                                             6,9-epoxy-7,16-difluoro-                                                      11,15-dihydroxy                                                               prost-5-en-1-oic acid                                                         methyl ester                                                              2.  Lactose Anhydrous                                                                              106.99  106.5 102.0 118.0                                3.  Avicel pH 102    15.0    15.0  15.0  25.0                                 4.  Modified starch  7.0     7.0   7.0   10.0                                 5.  Magnesium stearate                                                                             1.0     1.0   1.0   2.0                                                       130.0   130.0 130.0 130.0                                ______________________________________                                    

Manufacturing Procedure

1. Dissolve item 3 in item 2.

2. Add item 1 to the solution in Step 1 and mix until dissolved.

3. Fill in soft gelatin capsule.

EXAMPLE 24

    ______________________________________                                        DIRECT COMPRESSION FORMULATION                                                Ingredient      mg/cap                                                        ______________________________________                                        1.  [5Z,7beta,9alpha,                                                                             0.01    0.5   5.0   25.0                                      11alpha,15R,16S]-                                                             6,9-epoxy-7,16-di-                                                            fluoro-11,15-dihydroxy                                                        prosten-5-en-1-oic acid                                                       sodium salt                                                               2.  Lactose         101.99  101.5 97.0  118.0                                     Anhydrous DTG.sup.(a)                                                     3.  Avicel pH 102   20.0    20.0  20.0  25.0                                  4.  Modified starch 7.0     7.0   7.0   10.0                                  5.  Magnesium stearate                                                                            1.0     1.0   1.0   2.0                                                       130.0   130.0 130.0 130.0                                 ______________________________________                                    

Manufacturing Procedure

1. Prepare a premix of item 1 with part of item 2.

2. Add the mixture in Step 1 to the mixture of remainder of items 2, 3and 4 and mix for 10 minutes. Add item 5 and mix for 3 minutes; compressusing suitable punch on suitable press.

EXAMPLE 25

    ______________________________________                                        DIRECT COMPRESSION FORMULATION                                                Ingredient       mg/cap                                                       ______________________________________                                        1.  (5Z,7beta,9alpha,                                                                              0.01    0.5   5.0   25.0                                     11alpha,15R,16S)-                                                             6,9-epoxy-7,16-difluoro-                                                      11,15-dihydroxy                                                               prost-5-en-1-oic acid                                                         methyl ester                                                              2.  Lactose Anhydrous                                                                              101.99  101.5 97.0  118.0                                    DTG                                                                       3.  Avicel pH 102    20.0    20.0  20.0  25.0                                 4.  Modified starch  7.0     7.0   7.0   10.0                                 5.  Magnesium stearate                                                                             1.0     1.0   1.0   2.0                                                       130.0   130.0 130.0 180.0                                ______________________________________                                    

Manufacturing Procedure

1. Prepare a premix of item 1 with part of item 2.

2. Add the mixture in Step 1 to the mixture of remainder of items 2, 3and 4 and mix for 10 minutes. Add item 5 and mix for 3 minutes; compressusing suitable punch on suitable press.

EXAMPLE 26

    ______________________________________                                        Cream 0.05%                                                                   The following is the quantitative composition of drug:                                                    Reasonable                                        Ingredients      g/kg       Variations                                        ______________________________________                                        (5Z,7beta,9alpha,                                                                              0.525*     --                                                11alpha,15R,16S)-                                                             6,9-epoxy-7,16-difluoro-                                                      11,15-dihydroxy                                                               prost-5-en-1-oic acid                                                         methyl ester                                                                  Glycery Monostearate S.E..sup.1                                                                100.00      80-120                                           Polysorbate 60.sup.2                                                                           20.00      15-25                                             Cetyl Alcohol    50.00      40-60                                             Petrolatum       70.00      50-90                                             Methyl Paraben   1.50       1.25-1.75                                         Propyl Paraben   0.50       0.4-0.6                                           Propylene Glycol 200.00     150-250                                           Purified Water   574.055    525-625                                           Total            1016.58 gm                                                   ______________________________________                                         .sup.1 Arlacel 165                                                            .sup.2 Tween 60                                                               *3% excess of drug                                                       

EXAMPLE 27

    ______________________________________                                        Cream 0.05%                                                                   The following is the quantitative composition of drug:                                                     Reasonable                                       Ingredients       g/kg       Variations                                       ______________________________________                                        (5Z,7beta,9alpha,11alpha,-                                                                      0.525*     --                                               15R,16S)-6,9-epoxy-7-fluoro-                                                  11,15-dihydroxy prost-5-en-1-oic                                              acid methyl ester                                                             Glyceryl Monostearate S.E..sup.1                                                                100.00      80-120                                          Polysorbate 60.sup.2                                                                            20.00      15-25                                            Cetyl Alcohol     50.00      40-60                                            Petrolatum        70.00      50-90                                            Methyl Paraben    1.50       1.25-1.75                                        Propyl Paraben    0.50       0.4-0.6                                          Propylene Glycol  200.00     150-250                                          Purified Water    574.055    525-625                                          Total             1016.58 gm                                                  ______________________________________                                         .sup.1 Arlacel 165                                                            .sup.2 Tween 60                                                               *3% excess of drug                                                       

EXAMPLE 28

    ______________________________________                                        Cream 0.25%                                                                   The following is the quantitative composition of drug:                                                    Reasonable                                        Ingredients      g/kg       Variations                                        ______________________________________                                        (5Z,7beta,9alpha,                                                                              2.575*     --                                                11alpha,15R,16S)-                                                             6,9-epoxy-7,16-difluoro-                                                      11,15-dihydroxy                                                               prost-5-en-1-oic acid                                                         methyl ester                                                                  Glyceryl Monostearate S.E..sup.1                                                               100.00      80-120                                           Polysorbate 60.sup.2                                                                           20.00      15-25                                             Cetyl Alcohol    50.00      40-60                                             Petrolatum       70.00      50-90                                             Methyl Paraben   1.50       1.25-1.75                                         Propyl Paraben   0.50       0.4-0.6                                           Propylene Glycol 200.00     150-250                                           Purified Water   571.395    500-600                                           Total            1015.97 gm                                                   ______________________________________                                         .sup.1 Arlacel 165                                                            .sup.2 Tween 60                                                               *3% excess of drug                                                       

EXAMPLE 29

    ______________________________________                                        Cream 0.25%                                                                   The following is the quantitative composition of drug:                                                     Reasonable                                       Ingredients       g/kg       Variations                                       ______________________________________                                        (5Z,7beta,9alpha,11alpha,-                                                                      2.575*     --                                               15R,16S)-6,9-epoxy-7-fluoro-                                                  11,15-dihydroxy prost-5-en-1-oic                                              acid methyl ester                                                             Glyceryl Monostearate S.E..sup.1                                                                100.00      80-120                                          Polysorbate 60.sup.2                                                                            20.00      15-25                                            Cetyl Alcohol     50.00      40-60                                            Petrolatum        70.00      50-90                                            Methyl Paraben    1.50       1.25-1.75                                        Propyl Paraben    0.50       0.4-0.6                                          Propylene Glycol  200.00     150-250                                          Purified Water    571.395    500-600                                          Total             1015.97 gm                                                  ______________________________________                                         .sup.1 Arlacel 165                                                            .sup.2 Tween 60                                                               *3% excess of drug                                                       

EXAMPLE 30

    ______________________________________                                        Cream 0.25%                                                                   The following is the quantitative composition of drug:                                                    Reasonable                                        Ingredients      g/kg       Variations                                        ______________________________________                                        [5Z,7beta,9alpha,                                                                              5.150*     --                                                11alpha,15R,16S]-                                                             6,9-epoxy-7,16-di-                                                            fluoro-11,15-dihydroxy                                                        prosten-5-en-1-oic acid                                                       sodium salt                                                                   Glyceryl Monostearate S.E..sup.1                                                               100.00      80-120                                           Polysorbate 60.sup.2                                                                           20.00      15-25                                             Cetyl Alcohol    50.00      40-60                                             Petrolatum       70.00      50-90                                             Methyl Paraben   1.50       1.25-1.75                                         Propyl Paraben   0.50       0.4-0.6                                           Propylene Glycol 200.00     150-250                                           Purified Water   568.05     500-600                                           Total            1015.20 gm                                                   ______________________________________                                         .sup.1 Arlacel 165                                                            .sup.2 Tween 60                                                               *3% excess of drug                                                       

EXAMPLE 31

    ______________________________________                                        Cream 0.5%                                                                    The following is the quantitative composition of drug:                                                     Reasonable                                       Ingredients       g/kg       Variations                                       ______________________________________                                        (5Z,7beta,9alpha,11alpha,-                                                                      5.150*     --                                               15R,16S)-6,9-epoxy-7-fluoro-                                                  11,15-dihydroxy prost-5-en-1-oic                                              acid methyl ester                                                             Glyceryl Monostearate S.E..sup.1                                                                100.00      80-120                                          Polysorbate 60.sup.2                                                                            20.00      15-25                                            Cetyl Alcohol     50.00      40-60                                            Petrolatum        70.00      50-90                                            Methyl Paraben    1.50       1.25-1.75                                        Propyl Paraben    0.50       0.4-0.6                                          Propylene Glycol  200.00     150-250                                          Purified Water    568.05     475-575                                          Total             1015.20 gm                                                  ______________________________________                                         .sup.1 Arlacel 165                                                            .sup.2 Tween 60                                                               *3% excess of drug                                                       

We claim:
 1. A prostacyclin selected from the group consisting of acompound of the formula ##STR9## wherein R is hydrogen or lower alkyl,R₂ is hydrogen, methyl or fluoro; and R₂ ' is fluoro or trifluoromethyl;with the proviso that when R₂ ' is trifluoromethyl, R₂ is hydrogen ormethyl;pharmaceutically acceptable salts, optical antipodes andracemates thereof.
 2. The prostacyclin of claim 1 wherein R₂ is hydrogenand R₂ ' is fluoro.
 3. The prostacyclin of claim 2 wherein said compoundis 6,9-epoxy-7,16-difluoro-11,15-dihydroxy-prost-5-en-1-oic acid methylester.
 4. The prostacyclin of claim 2 wherein said compound is6,7-epoxy-7,16-difluoro-11,15-dihydroxy-prost-5-en-1-oic acid.
 5. Aprostacyclin selected from the group consisting of a compound of theformula: ##STR10## wherein R is hydrogen or lower alkyl, R₂ is hydrogen,methyl or fluoro; and R₂ ' is fluoro or trifluoromethyl; and with theproviso that when R₂ ' is trifluoromethyl, R₂ is hydrogen ormethyl;pharmaceutically acceptable salts, optical antipodes andracemates thereof.
 6. The prostacyclin of claim 5 wherein R₂ is hydrogenand R₂ ' is fluoro.
 7. The prostacyclin of claim 6 wherein said compoundis 6,9-epoxy-7,16-difluoro-11,15-dihydroxyprost-4-en-1-oic acid.
 8. Aintermediates selected from the group consisting of a compound of theformula: ##STR11## wherein R₆ is lower alkyl; R₅ is hydrogen ortri(lower)alkylsilyl; R₂ is methyl, hydrogen or fluoro; R₂ ' is fluoro,hydrogen, trifluoromethyl or methyl; and X is halogen; with the provisothat when R₂ ' is trifluoromethyl; R₂ is hydrogen or methyl;opticalantipodes and racemates thereof.
 9. The intermediates of claim 8 whereinR₂ ' and R₂ are hydrogen.
 10. The intermediate of claim 9 wherein saidcompound is 6,9-epoxy-7-fluoro-11,15-dihydroxy-5-iodo-prostanoic acidmethyl ester.
 11. The intermediate of claim 8 wherein R₂ is hydrogen andR₂ ' is fluoro.
 12. The intermediate of claim 11 wherein said compoundis 6,9-epoxy-7,16-difluoro-11,15-dihydroxy-5-iodoprostanoic acid methylester.